The oral administration of drugs as currently employed is unsatisfactory for a number of reasons. First, drugs with short half lives require frequent dosing (2 to 4 times daily), which can lead to inadequate compliance by the patient. Second, the short plasma half life of the drug and frequent dosing regimen result in "peaks" and "valleys" in the plasma concentration profile, which increases the likelihood of adverse side effects associated with the peak concentration as well as lapse of therapeutic effectiveness toward the end of the dosing interval. Third, the potential effect of hepatic first pass metabolism associated with oral administration could lead to poor bioavailibility of the drug. Thus, an effective and consistent drug delivery system that overcomes these disadvantages would be far superior to the current oral regimen.
Transdermal delivery of drugs provides many advantages over conventional oral administration. Advantages of transdermal systems include convenience, uninterrupted therapy, improved patient compliance, reversibility of treatment (by removal of the system from the skin), elimination of "hepatic first pass" effect, a high degree of control over blood concentration of the drug, and improved overall therapy.
Although transdermal systems have many advantages, most drugs are not amenable to this mode of administration due to the well known barrier properties of the skin. Molecules moving from the environment into and through intact skin must first penetrate the stratum corneum, the outer horny layer of the skin, and any material on its surface. The molecule must then penetrate the viable epidermis and the papillary dermis before passing through the capillary walls and into systemic circulation. Along the way, each of the above-mentioned tissues will exhibit a different resistance to penetration by the same molecule. However, it is the stratum corneum, a complex structure of compact keratinized cell remnants separated by extracellular lipid domains, that presents the greatest barrier to absorption of topical compositions or transdermally administered drugs. Compared to the oral or gastric mucosa, the stratum corneum is much less permeable to outside molecules.
The flux of a drug across the skin can be increased by changing either (a) the resistance (the diffusion coefficient), or (b) the driving force (the solubility of the drug in the stratum corneum and consequently the gradient for diffusion). Many enhancer compositions have been developed to change one or both of these factors. U.S. Pat. Nos. 4,006,218; 3,551,154; and 3,472,931, for example, respectively describe the use of dimethylsulfoxide (DMSO), dimethyl formamide (DMF), and N,N-dimethylacetamide (DMA) for enhancing the absorption of topically applied drugs through the stratum corneum. Combinations of enhancers consisting of diethylene glycol monoethyl or monomethyl ether with propylene glycol monolaurate and methyl laurate are disclosed in U.S. Pat. No. 4,973,468 as enhancing the transdermal delivery of steroids such as progestogens and estrogens. A dual enhancer consisting of glycerol monolaurate and ethanol for the transdermal delivery of drugs is shown in U.S. Pat. No. 4,820,720. U.S. Pat. No. 5,006,342 lists numerous enhancers for transdermal drug administration consisting of fatty acid esters or fatty alcohol ethers of C.sub.2 to C.sub.4 alkanediols, where each fatty acid/alcohol portion of the ester/ether is of about 8 to 22 carbon atoms. U.S. Pat. No. 4,863,970 shows penetration-enhancing compositions for topical application comprising an active permeant contained in a penetration-enhancing vehicle containing specified amounts of one or more cell-envelope disordering compounds such as oleic acid, oleyl alcohol, and glycerol esters of oleic acid; a C.sub.2 or C.sub.3 alkanol; and an inert diluent such as water.
Triacetin is known to be a solvent for solubilizing or diluting a drug and/or other components of drug delivery systems. For example, Mahjour et al., U.S. Pat. No. 4,879,297, disclose triacetin as a solvent in an enhancer system of propylene glycol and linoleic acid. Increasing amounts of triacetin and corresponding decreasing amounts of linoleic acid in the enhancer formulations correlate with decreasing flux and increasing lag time for permeation of the drug oxymorphone, suggesting that triacetin is relatively unimportant in the enhancer formulation. As another example, Ebert et al., WO9325168-A1, disclose triacetin as a solvent, in a list of many other solvents, to be used along with a cell-envelope disordering compound for the delivery of clonidine, progesterone, testosterone, and other drugs. Other patent documents that describe triacetin as a solvent include U.S. Pat. No. 4,908,389; U.S. Pat. No. 5,019,395; U.S. Pat. No. 4,666,926; U.S. Pat. No. 4,857,313; U.S. Pat. No. 4,789,547; U.S. Pat. No. 4,814,173; U.S. Pat. No. 4,783,450; EP-387647-A; JP63255227-A; JP62240628-A; and JP62215537-A.
Triacetin is also known as a plasticizer. For example, Edgren et al., U.S. Pat. No. 5,160,743, teach the use of triacetin as a conventional plasticizer to be used with an emulsifying agent in tablets, capsules, powders, and the like for gastrointestinal release of drugs. Other patent documents and publications that disclose use of triacetin as a plasticizer include Lin et al., 8 Pharm. Res. 1137 (1991); WO 9313753; EP 509335-A1; and JP3083917-A.
Triacetin has also been described to function as an antimicrobial agent. Allen, U.S. Pat. No. 4,895,727, teaches that triacetin has activity as an antifungal agent.
Triacetin has further been stated to contain activity as an absorption accelerator. Ikeda et al., WO9309783-A1, disclose a piroxicam-containing plaster for achieving an anti-inflammatory and analgesic effect due to absorption of piroxicam through the skin and state that triacetin enhances percutaneous absorption of piroxicam. The plaster is composed of a water-soluble polymeric adhesive; a glycol compound such as glycerin or propylene glycol; a cross-linking agent; water; an inorganic powder; and a surfactant, such as polyoxyethylene sorbitol monooleate, polyoxyethylene monooleate, sorbitol monooleate, or polyoxyethylene castor oil. It is further stated that, if necessary, penetration enhancers, preservatives, antioxidants, flavoring agents, and colorants can also be added to the formulation. The glycols and surfactants are classic solvents and cell-envelope disordering compounds known in the art of penetration enhancement, e.g. U.S. Pat. No. 4,855,294, thus the observed effects appear to result from the combination of glycol, surfactant, and triacetin.
Japanese patent document JP05148141-A describes a two-layer percutaneous absorption preparation containing an adhesive, isosorbide dinitrate, and an absorption accelerator. The absorption accelerators are stated to be glyceryl triesters wherein the fatty acid esters have chain lengths of 1 to 4 carbon atoms, triacetin being preferred. It should be recognized that isosorbide dinitrate has solubilizing properties of its own, i.e. it is a neutral, "solvent-acting drug," Sablotsky et al U.S., Patent No. 5,186,938. Other vasodilators, such as nitrate esters (--C--O--NO.sub.2) characterized by a sequence of carbon-oxygen-nitrogen and nitrite esters characterized by a (--C--O--NO) sequence, are among these solvent-acting drugs, including glyceryl trinitrate (erroneously called nitroglycerin according to its widespread and official designation), mannitol hexanitrate, erythritol tetranitrate, and pentaerythritol tetranitrate. Thus, the penetration enhancing effect of triacetin reported by JP05148141-A is shown only in conjunction with a neutral, solvent-acting drug.
What has not been previously shown is that triacetin is by itself an effective penetration enhancer for promoting the transdermal delivery of non-solvent-acting drugs, particularly of basic drugs having a pK.sub.a, of about 8.0 or greater and their acid addition salts. In view of the foregoing, it will be appreciated that compositions and methods for enhancing penetration of such basic drug and their acid addition salts would be a significant advancement in the art.